Acute Effects of Exogenous Ketone Ester Administration in Heart Failure

The purpose of this study is to test whether a ketone ester drink will improve exercise in people with heart failure (HF) compared to a placebo. In HF, patients are limited in their ability to do all the things they want to do, and exercise as much as they would like, due to becoming tired and short of breath early. There may be several reasons why these symptoms occur. There is some evidence that in addition to problems with the heart, patients with HF also have problems with their arteries and muscles that affect their ability to exercise. Ketones have been shown to improve exercise capacity in healthy volunteers, which may be related to effects on the heart function or on muscles. An infusion of ketones through an intravenous (IV) line has also been shown to significantly improve heart function, but whether a drink can produce similar improvements in HF patients is not known. This drink has been given status by Food and Drug Administration as "generally regarded as safe". The use of DeltaG in this study is experimental. DeltaG has not been approved by the Food and Drug Administration (FDA) for the use being evaluated in this study.

Overview: The overall study design will be a randomized, double-blind crossover comparison of ketone ester (KE) therapy vs. KE-free vehicle in 20 patients with established HF with preserved ejection fraction (HFpEF). The main outcomes will be measures of exercise performance (peak and submaximal exercise).

A nutraceutical ketone ester (KE), (R)-3-hydroxybutyl (R)-3-hydroxybutyrate which provides systemic ketosis

Submaximal exercise capacity (exercise time at 75% of peak workload) assessed by cardiopulmonary exercise testing.

Substrate utilization (reflected by the respiratory exchange ratio) assessed by cardiopulmonary exercise testing.

VO2 efficiency (total work performed over oxygen consumed) during submaximal cardiopulmonary exercise testing.

Left ventricular global longitudinal strain (%) assessed by echocardiography strain analysis at rest.

Inclusion criteria: Left ventricular ejection fraction ≥ 50% Evidence for elevated filling pressures as follows (at least one of the following between a-d): a. Mitral early (E)/mitral septal tissue annular (e') velocity ratio > 8 in addition to one of the following: i. Large left atrium (LA>4.0 cm width or LA volume index >34 mL/m2) ii. Chronic loop diuretic use for control of symptoms iii. Elevated natriuretic peptides within the past year (NT-proBNP>125 pg/ml or BNP>35 pg/ml) b. Mitral E/e' ratio > 1441 at rest or with exercise c. Elevated invasively-determined filling pressures previously (resting left ventricular end-diastolic pressure >16 mm Hg or pulmonary capillary wedge pressure > 15 mmHg; or PCWP/LVEDP ≥ 25 mmHg with exercise) d. Prior episode of acute heart failure requiring IV diuretics with evidence of volume overload on exam/radiology or elevated natriuretic peptides. Exclusion Criteria Intentional ketogenic (high fat, low carbohydrate) diet in the last week or use of ketogenic medications (SGLT2 inhibitors) Significant liver disease (liver function tests > 3x upper limit of normal, cirrhosis) or alcohol abuse disorder (>14 drinks/week). Contraindications to stress testing, conditions that limit exercise, and other clinically-significant causes of exertional limitation (claudication with peripheral artery disease, atrial fibrillation and heart rate >110 at rest, systolic blood pressure>180 mmHg or diastolic blood pressure>110 mmHg, infiltrative/hypertrophic/inflammatory cardiomyopathy, clinically significant pericardial disease, joint or neuromuscular disease that precludes exercise, acute coronary syndrome within the last 2 months, estimated glomerular filtration rate<30 mL/min/1.73 m2, and hemoglobin < 9 mg/dL). Clinically significant lung disease. This would be defined by severe obstructive lung disease (Gold stage 3), a requirement for supplemental oxygen, or chronic obstructive pulmonary disease with an exacerbation requiring steroids or antibiotics within the last 2 months. >= Moderate aortic stenosis, >mild mitral stenosis, >= moderate aortic or mitral regurgitation on screening echocardiogram Type 1 diabetes mellitus Pregnant women. Due to unknown affects of nutritional ketosis in pregnant women, pregnancy will be an exclusion. Accordingly, women of childbearing age with a menstrual cycle within the past year will be asked to submit a urine specimen for pregnancy testing. Angina due to epicardial coronary disease or known presence of clinically-significant, unrevascularized epicardial coronary disease, in the investigator's opinion. Prior reduced LVEF to < 45%